1. Technical Field
The present invention relates to novel heterocyclic compounds which inhibit the P2X7 receptor.
2. Background Art
The purinergic P2X7 receptor is a ligand-gated ion channel which becomes permeable to ions such as Ca2+ upon the binding of purine nucleotides and is expressed in macrophages, mast cells, T-lymphocytes, B-lymphocytes, antigen presenting cells, osteoclasts, keratinocytes and the like. It is associated with inflammatory and immunological diseases by mediating production of inflammatory cytokines, in particular IL-1β (interleukin-1β) (Non-patent documents 1 and 2). It is also expressed in microglia and associated with pain (Non-patent document 3).
Therefore, P2X7 receptor inhibitors can be useful for treatment of these diseases, and actually, it is known that P2X7 knockout mice are resistant to the development of experimental arthritis and pain and that P2X7 receptor inhibitors attenuate neuropathic pain (Non-patent documents 3 to 5).
Although several P2X7 receptor inhibitors have been known from the following reports (such as Patent documents 1 and 2), further development of such drugs is demanded.    Patent document 1: WO99/29660    Patent document 2: WO2007/109192    Non-patent document 1: Physiol. Rev. 2002: 82, p. 1013-1067    Non-patent document 2: J. Immunol. 2006: 176, p. 3877-3883    Non-patent document 3: Pain 2005: 114, p. 386-396    Non-patent document 4: J. Immunol. 2002: 168, p. 6436-6445    Non-patent document 5: J. Pharmacol. Exp. Ther. 2006: 319, p. 1376-1385